2016-12-09T15:34:22ZPhonological working memory and finiteness marking in typical developmenthttp://hdl.handle.net/1721.1/101316
Phonological working memory and finiteness marking in typical development
Ostrovskaya, Irina
The goal of this work was to characterize the maturational trajectory of two core developmental language functions: phonological working memory (PWM) as indexed on nonword repetition (NWR) tasks, and finiteness-related grammatical processing, as indexed by grammaticality judgment. These fundamental language abilities make particularly alluring candidates for investigation due to their central role in language development and academic achievement as well as their theoretical basis. Moreover, PWM and finiteness-marking appear to have genetic bases (e.g., Bishop, Adams, & Norbury, 2006) are powerful markers of language impairment (Conti-Ramsden, Botting, & Faragher, 2001), highlighting the clinical significance of these abilities. PWM, the capacity to temporarily store and flexibly operate on units of auditory information in the service of a goal, is a developmental ability central to language acquisition. As assessed using NWR tasks, PWM has been shown to be instrumental for the development of both spoken and written language (e.g., Baddeley, Gathercole, & Papagano, 1998), and weaknesses in this system are not only associated with problems of language and literacy but are a common correlate of communication deficits in a number of developmental disorders. Despite their demonstrated clinical and theoretical significance, however, there is a surprising paucity of studies examining NWR in a wide, continuous age range including childhood and young adulthood. In the current work, we administered several assessments of NWR to a wide sample of typically-developing children and adults age 5-35 in order to discover the shape of the developmental trajectory of this skill and the age at which proficient levels of performance are achieved. Across several measures varying in the nature and length of the stimuli, the maturational trajectory of NWR was characterized by rapid growth for younger ages which sharply transitions to relatively stable levels. The transitional age between mature and immature performance was found to lie in the 8-11 year old age range, suggesting that NWR ability develops over the later elementary school years. Consistent with prior work, the effect of stimulus length was greater in younger participants, and the tasks involving stimuli which do not resemble real English words were found to be more challenging for all ages than those involving wordlike stimuli. The ability to appropriately mark tense on verbs is also crucial to language development. Children in the Optional Infinitive (01) stage of language acquisition interchangeably use finite (marked for tense and agreement) and non-finite (infinitival) verb forms in clauses requiring finiteness; likewise, both finite and non-finite forms are accepted as grammatically correct in clauses mandating the finite form. Although appropriate use of finiteness has previously been thought to be in place by the time children enter formal schooling (Rice & Wexler, 1996), our recent work (Kovelman et al., 2014) challenged this notion, as linguistically-proficient adults found sentences containing finiteness errors more difficult to process than sentences containing non-developmental agreement errors or grammatically correct sentences. As yet, no one has examined the continuous progression of 01-related processing from early childhood to adulthood using a receptive (or any) measure. In order to discover the shape of the maturational trajectory of finiteness processing and the age at which proficient performance is achieved, in the current work, we administered a grammaticality judgment task involving sentences with developmental errors of finiteness and control grammatical errors to a large sample of typically developing participants age 5-35. Similar to the case of NWR, the shape of the maturational trajectory of finiteness was marked by initially rapid growth transitioning to stable performance. Not only were sentences with errors of finiteness found to be more difficult than those with non-developmental errors, but this condition was characterized by slower developmental growth and an older transition to mature performance than other conditions. Adult-like levels of performance on sentences with finiteness errors were achieved around age 8, suggesting a more protracted developmental course for this ability than previously believed (c.f. Rice, Wexler, & Hershberger, 1998). Taken together, it is hoped that this work will increase our understanding of the developmental trajectories of finiteness-based grammatical processing and PWM. We hope this work will impact early identification of weaknesses in these systems such that appropriate interventions can be implemented.
Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015.; Cataloged from PDF version of thesis.; Includes bibliographical references (pages 137-171).
2015-01-01T00:00:00ZSingle-molecule visualization of conformational changes in the SecA ATPasehttp://hdl.handle.net/1721.1/98721
Single-molecule visualization of conformational changes in the SecA ATPase
Sargent, Jacob D. (Jacob Daniel)
The need for new antibiotics is great as bacterial strains with single and multiple drug resistance have continued to grow more prevalent since the 1980's. At the same time, the rate of approval of new antibiotics has dropped precipitously. Existing antibiotics commonly target the bacterial ribosome. A or cell wall synthetic pathways: two targets that are essential for bacterial survival. However, another option is to target a pathway which is more intimately connected to bacterial pathogenesis: protein secretion. In bacteria, most secreted polypeptides are pushed across the membrane, via the SecYEG channel, by the SecA ATPase. Relatively little is understood of how SecA couples ATP hydrolysis to polypeptide translocation. X-ray crystallography and many biochemical studies support a model in which the two-helix finger (2HF) of SecA pushes the polypeptide through the SecYEG channel, however some evidence is contradictory. We aim to directly measure conformational changes of the 2HF by utilizing single-molecule Fbrster resonance energy transfer (smFRET). Directly measuring conformational changes in an ATPase will also provide further insight into the guiding principles of ATPase function. First, we will build a smFRET microscope and assemble a software package to analyze the data it collects. We will then validate these tools by reproducing results currently in the literature from Holden et al. and McKinney et al.. Next, we will assess the potential limitations of current tools for smFRET data analysis, especially as applied to ATPases. We will propose a new approach that may be useful in these systems. Finally, we will use the smFRET microscope to measure ATP-dependent conformational dynamics of the 2HF. This evidence will help differentiate between three proposed models: the 2HF (1) is not directly involved in polypeptide translocation, (2) moves unidirectionally, directly driving translocation, or (3) moves back and forth but in a way that is coordinated by ATP hydrolysis with progress capture elsewhere in SecA.
Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015.; Cataloged from PDF version of thesis.; Includes bibliographical references (pages 36-39).
2015-01-01T00:00:00ZUse of wearable ambulatory monitor in the classification of movement states in Parkinson's diseasehttp://hdl.handle.net/1721.1/98336
Use of wearable ambulatory monitor in the classification of movement states in Parkinson's disease
Klapper, David A. (David Asher), 1966-
For Parkinson's patients to function at their best, their medications need to be optimally adjusted to the diurnal variation of symptoms. For this to occur, it is important for the managing clinician to have an accurate picture of how the patient's bradykinesia/hypokinesia and dyskinesia fluctuate throughout the normal daily activities. This thesis proposes the use of wearable accelerometers coupled with machine learning and statistical techniques in order to classify the movement states of Parkinson's patients and to provide a timeline of how the patients fluctuate throughout the day. A pilot study was performed using 2 patients with the goal of assessing the ability to classify dyskinesia and bradykinesia/hypokinesia based on accelerometric data. The patients were observed and videotaped. Clinical observations of bradykinesia/hypokinesia and dyskinesia were noted every minute. Neural networks were able to classify better than classification trees with an average c-index (equivalent to the area under the ROC curve) of 0.905 for bradykinesia/hypokinesia and 0.926 for dyskinesia. A separate group of 5 patients were observed with the additional goal of building models that can classify the movement of a patient without requiring clinically annotated training data for the same patient. An enhanced protocol was used in the final study. Dichotomized linear regression was found to classify well with an average c-index of 0.8219 for body bradykinesia/hypokinesia and 0.8799 using as the gold-standard the patient's diary. Dyskinesia was classified at a c-index of 0.7522. Neural networks did not perform as well, possibly because of restrictions placed on adjusting parameters. The two most clinically important problems: predicting; (cont.) when the patient feels he/she is "off' or when he/she has "troublesome dyskinesia" were discriminated with c-indices of 0.96 and 1.0 respectively. The good result of the models despite the small number of patients is promising. Further studies with larger number of patients are therefore justified.
Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, September 2003.; "August 2003."; Includes bibliographical references (p. 54-57).
2003-01-01T00:00:00ZNovel endoscopes for microscopic assessment of airway clearance using micro-optical coherence tomographyhttp://hdl.handle.net/1721.1/97830
Novel endoscopes for microscopic assessment of airway clearance using micro-optical coherence tomography
Unglert, Carolin Isabella
The health of the human respiratory system depends critically on airway clearance via motile hair-like structures (cilia), which transport and eliminate unwanted particles trapped within mucus. Impairment of mucociliary clearance (MCC) can lead to life-threatening airway narrowing and lung infections, and is a major cause of morbidity and mortality in patients with cystic fibrosis, primary ciliary dyskinesia and chronic obstructive lung disease. However, no tool for microscopic in-vivo visualization of ciliary function is currently available, limiting studies of disease pathogenesis, refined diagnosis and phenotyping, and the development of novel therapeutics. In this thesis, a novel, 1-pm resolution, optical interferometric imaging technique termed Micro-OCT was incorporated into miniaturized common-path endoscopes and mucociliary transport was visualized in vivo for the first time. The first-generation Micro-OCT probe had a rigid design with outer diameter of 4 mm and a two-prism configuration providing beam splitting and sample beam shaping into an annular profile. Image quality of the probe allowed visualization of the periodic pattern of ciliary beating, measurement of airway surface liquid depth (ASL) and visualization of mucociliary transport. Unaltered ciliary function was demonstrated in a living, spontaneously breathing swine model. Newer generation common-path endoscope designs were demonstrated that improve, among other limitations, the stability of the reference reflector position and provide greater potential for miniaturization. The presented work opens unprecedented avenues for studying MCC and the effect of novel therapeutics within the complexity of a living organism. Further, it lays the groundwork for the development of a human probe with the potential to revolutionize diagnosis, phenotyping, and therapy management for all patients with respiratory disease involving the mucociliary escalator.
Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015.; Cataloged from PDF version of thesis.; Includes bibliographical references (pages 73-77).
2015-01-01T00:00:00Z